Phase i trials using sleeping beauty to generate CD19-specific CAR T cells

Partow Kebriaei, Harjeet Singh, M. Helen Huls, Matthew J. Figliola, Roland Bassett, Simon Olivares, Bipulendu Jena, Margaret J. Dawson, Pappanaicken R. Kumaresan, Shihuang Su, Sourindra Maiti, Jianliang Dai, Branden Moriarity, Marie Andrée Forget, Vladimir Senyukov, Aaron Orozco, Tingting Liu, Jessica McCarty, Rineka N. Jackson, Judy S. MoyesGabriela Rondon, Muzaffar Qazilbash, Stefan Ciurea, Amin Alousi, Yago Nieto, Katy Rezvani, David Marin, Uday Popat, Chitra Hosing, Elizabeth J. Shpall, Hagop Kantarjian, Michael Keating, William Wierda, Kim Anh Do, David A. Largaespada, Dean A. Lee, Perry B. Hackett, Richard E. Champlin, Laurence J N Cooper

Research output: Contribution to journalArticle

174 Scopus citations

Abstract

BACKGROUND. T cells expressing antigen-specific chimeric antigen receptors (CARs) improve outcomes for CD19-expressing B cell malignancies. We evaluated a human application of T cells that were genetically modified using the Sleeping Beauty (SB) transposon/transposase system to express a CD19-specific CAR. METHODS. T cells were genetically modified using DNA plasmids from the SB platform to stably express a second-generation CD19-specific CAR and selectively propagated ex vivo with activating and propagating cells (AaPCs) and cytokines. Twenty-six patients with advanced non-Hodgkin lymphoma and acute lymphoblastic leukemia safely underwent hematopoietic stem cell transplantation (HSCT) and infusion of CAR T cells as adjuvant therapy in the autologous (n = 7) or allogeneic settings (n = 19). RESULTS. SB-mediated genetic transposition and stimulation resulted in 2,200- to 2,500-fold ex vivo expansion of genetically modified T cells, with 84% CAR expression, and without integration hotspots. Following autologous HSCT, the 30-month progression-free and overall survivals were 83% and 100%, respectively. After allogeneic HSCT, the respective 12-month rates were 53% and 63%. No acute or late toxicities and no exacerbation of graft-versus-host disease were observed. Despite a low antigen burden and unsupportive recipient cytokine environment, CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients. CONCLUSIONS. CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional cancer control as planned infusions after HSCT. These results support further clinical development of this nonviral gene therapy approach.

Original languageEnglish (US)
Pages (from-to)3363-3376
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number9
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

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Kebriaei, P., Singh, H., Huls, M. H., Figliola, M. J., Bassett, R., Olivares, S., Jena, B., Dawson, M. J., Kumaresan, P. R., Su, S., Maiti, S., Dai, J., Moriarity, B., Forget, M. A., Senyukov, V., Orozco, A., Liu, T., McCarty, J., Jackson, R. N., ... Cooper, L. J. N. (2016). Phase i trials using sleeping beauty to generate CD19-specific CAR T cells. Journal of Clinical Investigation, 126(9), 3363-3376. https://doi.org/10.1172/JCI86721